The invention relates to crystal forms of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide; processes for the production thereof; pharmaceutical compositions thereof; and methods of treating glycogen phosphorylase dependent diseases, or conditions, therewith.
Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of, and use of, sulfonylureas (e.g. Chlorpropamide(trademark) (Pfizer), Tolbutamide(trademark) (Upjohn), Acetohexamide(trademark) (E. I. Lilly), Tolazamide(trademark) (Upjohn), and biguanides (e.g. Phenformin(trademark) (Ciba Geigy), and Metformin(trademark) (G. D. Searle)) as oral hypoglycemic agents, therapeutic regimens for the treatment of diabetes remain less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type 1 diabetes, insulin dependent diabetes mellitus), requires multiple daily doses, usually by self-injection. Determination of the proper dosage of insulin requires frequent estimations of sugar levels in the urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type 2 diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and, in more severe cases, insulin. However, clinically available hypoglycemic agents can have other side effects that limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerotic development and occlusive heart disease is well known. The earliest stage in this sequence is the formation of xe2x80x9cfatty streaksxe2x80x9d in the carotid, coronary, and cerebral arteries, and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. It is further postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to development of the so-called xe2x80x9cfibrous plaquexe2x80x9d, which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin, and proteoglycans. These cells, plus matrix, form a fibrous cap that covers a deeper deposit of cell debris and more extra cellular lipid, which comprises primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the so-called xe2x80x9ccomplicated lesionxe2x80x9d which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, medical professionals have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of so-called xe2x80x9cnormalxe2x80x9d cholesterol are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now recognized to be at particular high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being male. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (high blood pressure) is a condition that occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent, or disorder, is unknown. While such essential hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients present with symptoms of high blood pressure in the complete absence of any other signs of disease, or disorder.
It is known that hypertension can directly lead to heart failure, renal failure, and stroke, which conditions are all capable of causing short-term death. Hypertension also contributes to the development of atherosclerosis, and coronary disease, which conditions gradually weaken a patient and can lead, in long-term, to death.
The precise etiology of essential hypertension is unknown, although a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin, aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in vascular constriction, and genetic pre-disposition.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus, a broad range of xcex2-blockers, vasoconstrictors, angiotensin converting enzyme (ACE) inhibitors, and the like have been developed and marketed as antihypertensive agents. The treatment of hypertension utilizing such agents has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure, and brain hemorrhaging (stroke). However, the development of atherosclerosis, or heart disease due to hypertension over a long period of time, remains a problem. This implies that, although high blood pressure is being reduced, the underlying cause of essential hypertension remains unresponsive to this treatment.
Hypertension has further been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis, and the formation and storage of neutral lipids, also acts, inter alia, to promote vascular cell growth and increase renal sodium retention. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries; while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviate hypertension.
Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction, and congestive heart failure. These cardiac events are due, at least in part, to increased susceptibility to myocardial injury after ischemia and reperfusion which can occur in both out-patient and periopeirative settings. There is currently an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both cardiac and non-cardiac surgery are associated with substantial risks for myocardial infarction or death, and some 7 million patients undergoing non-cardiac surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some instances. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no commercial drug therapy in this area which reduces damage :to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients. The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood, however, it has been reported (M. F. Allard, et al. Am. J. Physiol., 267, H66-H74, (1994) that pre-ischemic glycogen reduction is associated with improved post-ischemic left ventricular functional recovery in hypertrophied rat hearts.
Hepatic glucose production is an important target for Type 2 diabetes therapy. The liver is the major regulator of plasma glucose levels in the post absorptive (fasted) state, and the rate of hepatic glucose production in Type 2 diabetes patients is significantly elevated relative to normal individuals. Likewise, in the postprandial (fed) state, where the liver has a proportionately smaller role in the total plasma glucose supply, hepatic glucose production is abnormally high in Type 2 diabetes patients.
Glycogenolysis is an important target for interruption of hepatic glucose production. The liver produces glucose by glycogenolysis (breakdown of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Several lines of evidence indicate that glycogenolysis may make an important contribution to hepatic glucose output in Type 2 diabetes. First, in normal post absorptive man, up to 75% of hepatic glucose production is estimated to result from glycogenolysis. Second, patients having liver glycogen storage diseases, including Hers"" disease (glycogen phosphorylase deficiency), display episodic hypoglycemia. These observations suggest that glycogenolysis may be a significant process for hepatic glucose production.
Glycogenolysis is catalyzed in liver, muscle, and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme cleaves the glycogen macromolecule releasing glucose-1-phosphate and a new shortened glycogen macromolecule. Two types of glycogen phosphorylase inhibitors have been reported to date: glucose and glucose analogs [J. L. Martin, et al., Biochemistry, 30, 10101, (1991)], and caffeine and other purine analogs [P. J. Kasvinsky, et al., J. Biol. Chem., 253, 3343-3351 and 9102-9106 (1978)]. These compounds, and glycogen phosphorylase inhibitors in general, have been postulated to be of potential use for the treatment of Type 2 diabetes by decreasing hepatic glucose production and lowering glycemia. See, for example, T. B. Blundell, et al., Diabetologia, 35 (Suppl. 2), 569-576 (1992), and Martin et al., supra.
Recently, glycogen phosphorylase inhibitors have been disclosed in, inter alia, PCT International Application Publication No. WO 97/31901, and in commonly-assigned U.S. Pat. Nos. 6,107,329, 6,277,877, and 6,297,269. The commonly-assigned U.S. Pat. Nos. 6,107,329, 6,277,877, and 6,297,269, the disclosures of which are incorporated herein by reference in their entirety, disclose novel substituted N-(indole-2-carbonyl)-xcex2-alaninamide compounds, including 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, denoted hereinbelow as the compound of Formula (I); certain derivatives thereof; processes for the production thereof; pharmaceutical compositions comprising such compounds or such derivatives; and methods of treating glycogen phosphorylase dependent diseases or conditions by administering such compounds, such pharmaceutical compositions, or such derivatives, to a mammal in need of such treatment.
The present invention relates to crystal forms of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide; processes for the production thereof, pharmaceutical compositions comprising such polymorphs; and uses thereof.